1. Field of the Invention
The present invention relates generally to methods of using anti-NGF antibodies in the treatment of various NGF-related disorders, including asthma, arthritis and psoriasis. The methods are effective in treating these disorders in a patient without having a significant adverse effect on the immune system of the patient.
2. Description of the Related Art
Nerve Growth Factor (NGF)
Nerve growth factor (NGF) was the first neurotrophin to be identified, and its role in the development and survival of both peripheral and central neurons has been well characterized. NGF has been shown to be a critical survival and maintenance factor in the development of peripheral sympathetic and embryonic sensory neurons and of basal forebrain cholinergic neurons (Smeyne et al., Nature 368:246-249 (1994); Crowley et al., Cell 76:1001-1011 (1994)). NGF upregulates expression of neuropeptides in sensory neurons (Lindsay and Harmer, Nature 337:362-364 (1989)) and its activity is mediated through two different membrane-bound receptors. The TrkA tyrosine kinase receptor mediates high affinity binding and the p75 receptor, which is structurally related to other members of the tumor necrosis factor receptor family, mediates low affinity binding (Chao et al., Science 232:518-521 (1986)).
In addition to its effects in the nervous system, NGF has been increasingly implicated in processes outside of the nervous system. For example, NGF has been shown to enhance vascular permeability (Otten et al., Eur. J. Pharmacol. 106:199-201 (1984)), enhance T- and B-cell immune responses (Otten et al., Proc. Natl. Acad. Sci. U.S.A. 86:10059-10063 (1989)), induce lymphocyte differentiation and mast cell proliferation and cause the release of soluble biological signals from mast cells (Matsuda et al., Proc. Natl. Acad. Sci. U.S.A. 85:6508-6512 (1988); Pearce et al., J. Physiol. 372:379-393 (1986); Bischoff et al., Blood 79:2662-2669 (1992); Horigome et al., J. Biol. Chem. 268:14881-14887 (1993)).
NGF is produced by a number of cell types including mast cells (Leon et al., Proc. Natl. Acad. Sci. U.S.A. 91:3739-3743 (1994)), B-lymphocytes (Torcia et al., Cell 85:345-356 (1996), keratinocytes (Di Marco et al., J. Biol. Chem. 268:22838-22846)) and smooth muscle cells (Ueyama et al., J. Hypertens. 11:1061-1065 (1993)). NGF receptors have been found on a variety of cell types outside of the nervous system. For example, TrkA has been found on human monocytes, T- and B-lymphocytes and mast cells.
Consistent with a non-neuronal role for NGF, an association between increased NGF levels and a variety of inflammatory conditions has been observed in human patients as well as in several animal models. These include systemic lupus erythematosus (Bracci-Laudiero et al., Neuroreport 4:563-565 (1993)), multiple sclerosis (Bracci-Laudiero et al., Neurosci. Lett. 147:9-12 (1992)), psoriasis (Raychaudhuri et al., Acta Derm. Venereol. 78:84-86 (1998)), arthritis (Falcini et al., Ann. Rheum. Dis. 55:745-748 (1996)) and asthma (Braun et al., Eur. J. Immunol. 28:3240-3251 (1998)). Chronic inflammatory conditions such as these are a significant public health problem. For instance, it is estimated that arthritis affects 37.9 million people in the United States alone. Current therapies for treating these conditions are severely limited. An understanding of the role NGF plays in these diseases may provide new methods for treating them.
A correlation between stress and psoriasis has been observed. Based on this correlation and the symmetry of the cutaneous lesions that accompany the disease, a relationship with the nervous system has been proposed (Raychaudhuri et al., Acta Derm. Venercol. 78:84-86 (1998)). In particular, neuropeptides have been suggested to play a role in the pathogenesis of psoriasis. Investigators have reported an increased number of terminal cutaneous nerves along with upregulation of one or more of the neuropeptides, such as substance P (SP), vasoactive intestinal polypeptide (VIP) and CGRP. NGF plays a role in regulating innervation in the skin and also is known to upregulate neuropeptides, suggesting that increased NGF levels may be responsible for the upregulation of neuropeptides and the increased cutaneous innervation seen with psoriasis. In fact, increased expression of NGF has been observed in psoriatic keratinocytes (Raychaudhuri et al., Acta Derm. Venercol. 78:84-86 (1998)). It has been suggested that while NGF normally serves as a survival factor for keratinocytes, overexpression of NGF prevents normal cell death, leading to psoriasis (Pincelli at al., J. Derm. Sci. 22:71-79 (2000)).
A number of studies have indicated that neuropeptides such as substance P (SP) and biologically active compounds released from mast cells, such as histamine, also play a role in both naturally occurring arthritis in humans and experimentally induced arthritis in animal models (see e.g. Levine, J., Science 226:547-549 (1984)). NGF has been shown to affect mast cell degranulation (Bruni at al., FEBS Lett. 138:190-193 (1982)) and substance P release (Donnerer et al., Neurosci. 49:693-698 (1992)), implicating it in the pathogenesis of arthritis.
Consistently, an elevated level of NGF in peripheral tissues is associated with both hyperalgesia and inflammation and has been observed in a number of forms of arthritis. The synovium of patients affected by rheumatoid arthritis expresses high levels of NGF while in non-inflamed synovium NGF has been reported to be undetectable (Aloe et al., Arch. Rheum. 35:351-355 (1992)). Similar results were seen in rats with experimentally induced rheumatoid arthritis (Aloe et al., Clin. Exp. Rheumatol. 10:203-204 (1992)). Elevated levels of NGF have been reported in transgenic arthritic mice along with an increase in the number of mast cells. (Aloe et al., Int. J. Tissue Reactions-Exp. Clin. Aspects 15:139-143 (1993)). However, purified NGF injected into the joint synovium of normal rats does not induce knee joint inflammation, suggesting that NGF does not play a causative role in arthritis (Aloe et al., Growth Factors 9:149-155 (1993)).
High NGF levels have been associated with allergic inflammation and it has been suggested that this is related to mast cell degranulation (Bonini et al., Proc. Natl. Acad. Sci. U.S.A. 93:10955-10960 (1996)).
Elevated NGF levels are also observed in both allergic and non-allergic asthma (Bonini et al., supra). Mast cells, eosinophils and T-lymphocytes have all been proposed to play a role in this inflammatory disease and the correlation between NGF serum levels and total IgE antibody titers suggests that NGF contributes to the inflammatory immune response. Allergen induced airway inflammation has been associated with increased local production of NGF in both mice and humans (Braun et al., Int. Arch. Allergy Immunol. 118:163-165 (1999)).
NGF has been shown to regulate the development of increased airway hyperactive response, a hallmark of bronchial asthma (Braun et al., Eur. J. Immunol. 28:3240-3251 (1998)). Indeed, in one study, treatment of allergen-sensitized mice with anti-NGF antibody prevented the development of airway hyperresponsiveness following local allergen challenge (Braun et al., Int. Arch. Allergy Immunol. 118:163-165 (1999)).
Despite the promising results obtained in mice, reported adverse effects of neutralizing anti-NGF antibodies on the immune system have raised serious questions about the feasibility of using anti-NGF antibodies as a therapeutic in the prevention or treatment of asthma or other diseases or disorders in human patients. In particular, Torcia at al., Cell 85:345-356 (1996) identified NGF as an autocrine survival factor for memory B lymphocytes, and demonstrated that in vivo administration of neutralizing anti-NGF antibodies caused a depletion of memory B-cells and abolished secondary antigen-specific immune responses in mice. Garaci et al., Proc. Natl. Acad. Sci. USA 96:14013-14018 (1999) reported that NGF is an autocrine survival factor that rescues human monocytes/macrophages from the cytopathic effect caused by HIV infection. This report, along with the findings of Torcia et al., supra would suggest that anti-NGF antibodies have the potential of compromising the immune system of the subject treated.